The molecular neuropathogenesis of HIV-1 infection revolves around viral replication in brain macrophages, microglia and multinucleated giant cells. Over the past decade, we began to unravel this unique virus-brain cell interaction and developed laboratory assay systems to identify macrophage secretory products (cellular and viral) that influence central nervous system (CNS) injury. We hypothesized that HIV-1 infection and cellular activation are both required for macrophages to secrete neurotoxic factors [(nitric oxide, eicosanoids, platelet-activating factor, excitatory amino acids, and proinflammatory cytokines (TNFalpha, IL-1beta and IL-6)]. These, taken together, mediate CNS pathology and influence the transendothelial migration of virus-infected monocytes across the blood brain barrier. During the next three years, we hope to further develop our laboratory and animal model systems for HIV encephalitis to determine the composition of neurotoxins and their role(s) in brain pathology. This may be accomplished by: (1) defining the interactions between HIV-1-infected macrophages and neural cells that are critical for neurotoxin production; (2) developing laboratory and animal model systems that assay neurovirulence of HIV-1; and (3) using this information to uncover novel therapeutics for treatment of the AIDS dementia complex. These aims will build upon our hypothesis that secretory factor from HIV-1-infected macrophages strongly influence viral neuropathogenesis. The elucidation of brain macrophage/microglial infection will inevitably provide the means to ameliorate cognitive and motor abnormalities in affected humans.